Neuropeptides and peptide hormones represent the largest class of chemical messengers that transmit information from one cell to another. In this review, several decades of research on peptides in cell-cell signaling are summarized, with a focus on neuropeptide discovery, biosynthesis, and function. In addition to covering the well-studied aspects of neuropeptides, emerging concepts are discussed, including classical versus non-classical neuropeptides and direct versus indirect neuropeptides. Other potential functions for peptides in intercellular and intracellular signaling are also discussed.